Michiie Sakamoto

Publications (170)703.01 Total impact

• Article: Low papillary structure in lepidic growth component of lung adenocarcinoma: a unique histologic hallmark of aggressive behavior.

  Toshinori Fukutomi, Yuichiro Hayashi, Katsura Emoto, Kazunori Kamiya, Mitsutomo Kohno, Michiie Sakamoto
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  ABSTRACT: Small-sized lung adenocarcinomas often contain a lepidic growth component in part. The term lepidic growth has recently been used to represent a growth pattern of neoplastic cells along preexisting alveolar structures. We reviewed 91 small-sized (≤3 cm) invasive lung adenocarcinomas with a lepidic component to study the histopathologic and clinicopathologic characteristics. In the lepidic component of invasive adenocarcinoma, we have identified a morphologically unique structure characterized by proliferation of low papillae, consisting of neoplastic cells piling up toward the alveolar space, and we defined this architecture as "low papillary structure." There were 18 cases with the low papillary structure in the lepidic components, whereas 73 cases did not have the structure. In the lepidic component, the cases with the low papillary structure had higher Ki-67 labeling index (15.7%) and more frequent p53 overexpression (50.0%) than did those without the structure (9.4% and 16.4%, respectively). Based on clinicopathologic findings, the presence of low papillary structure was significantly associated with lymphatic invasion (P = .023) and lymph node metastasis (P = .001). Furthermore, the patients with the low papillary structure in the lepidic components demonstrated significantly shorter disease-free and overall survival than did those without the structure (P = .001 and P = .010, respectively). We conclude that the low papillary structure is a significant histologic feature in a lepidic component and is associated with aggressive cancer behavior in lung adenocarcinoma.
  Human pathology 05/2013; · 3.03 Impact Factor
• Article: Progressive liver failure induced by everolimus for renal cell carcinoma in a 58-year-old male hepatitis B virus carrier.

  Shinta Mizuno, Yoshiyuki Yamagishi, Hirotoshi Ebinuma, Nobuhiro Nakamoto, Mai Katahira, Aya Sasaki, Michiie Sakamoto, Hidekazu Suzuki, Takanori Kanai, Toshifumi Hibi
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  ABSTRACT: A 58-year-old man was diagnosed as a hepatitis B virus (HBV) carrier approximately 30 years ago. He was diagnosed with renal cell carcinoma when he was 57 years old. Radical nephrectomy was performed, and everolimus was administered to treat his lung metastasis. After beginning the everolimus, intermittent fever, general fatigue, and jaundice developed. He was admitted under a diagnosis of flare (acute exacerbation) of chronic B hepatitis due to HBV reactivation. Despite intensive care, he died of hepatic failure and fungus infection. The autopsy findings were compatible with hepatic failure due to HBV reactivation by everolimus. Antiviral prophylaxis must be taken into consideration before beginning immunosuppressive therapy such as everolimus in HBV carriers.
  Clinical Journal of Gastroenterology 04/2013; 6(2):188-192.
• Article: Mitochondrial metabolism in the noncancerous liver determine the occurrence of hepatocellular carcinoma: a prospective study.

  Atsushi Kudo, Kaoru Mogushi, Tadatoshi Takayama, Satoshi Matsumura, Daisuke Ban, Takumi Irie, Takanori Ochiai, Noriaki Nakamura, Hiroshi Tanaka, Naohiko Anzai, Michiie Sakamoto, Shinji Tanaka, Shigeki Arii
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  ABSTRACT: BACKGROUND: Recurrence determines the postoperative prognosis with hepatocellular carcinoma (HCC). It is unknown how the liver dysfunction involving organic anion transporter failure causes the occurrence of HCCs. This study was designed to elucidate the link between liver dysfunction and multicentric occurrence (MO) after radical hepatectomy. METHODS: Forty-nine samples of noncancerous liver tissue from HCC patients within the Milan criteria who were treated at our institution between January 2004 and August 2008 were examined as a training set by using genome-wide gene expression analysis. Using the independent 2-institutional cohort of 134 patients between September 2008 and December 2009, we performed a validation study using tissue microarray analysis. Cox proportional hazard regression analyses for MFS were performed to estimate the risk factors. RESULTS: In the Gene Ontology database (GO:0015711), SLC22A7 expression was the best predictor of MO-free survival [MFS] (Fold, 0.726; P = 0.001). High SLC22A7 gene expression prevented the occurrence of HCC after hepatectomy (odds ratio [OR], 0.2; P = 0.004). Multivariate analyses identified SLC22A7 expression as an independent risk factor (OR, 0.3; P = 0.043). In the validation study, multivariate analyses of MFS identified SLC22A7 expression as an independent risk factor (OR, 0.5; P = 0.012). As judged by gene set enrichment analysis, SLC22A7 down regulation was associated with mitochondrion (P = 0.008) and oxidoreductase activity (P = 0.006). Sirtuin 3 as a regulator of mitochondrial metabolism also determined MFS (P = 0.018). CONCLUSIONS: The mitochondrial pathways may affect SLC 22A7 function to promote the occurrence of HCC. (Word count: 246).
  Journal of Gastroenterology 03/2013; · 4.16 Impact Factor
• Article: Impact of Histologically Confirmed Lymph Node Metastases on Patient Survival After Surgical Resection for Hepatocellular Carcinoma: Report of a Japanese Nationwide Survey.

  Kiyoshi Hasegawa, Masatoshi Makuuchi, Norihiro Kokudo, Namiki Izumi, Takafumi Ichida, Masatoshi Kudo, Yonson Ku, Michiie Sakamoto, Osamu Nakashima, Osamu Matsui, Yutaka Matsuyama
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  ABSTRACT: OBJECTIVE:: To clarify the clinical significance of resection of lymph node metastases in patients' hepatocellular carcinoma (HCC). BACKGROUND:: Although the presence of lymph node metastasis form HCC has been considered as a systemic disease, prognosis after resection of them remains unknown. METHODS:: From the database of a Japanese nationwide survey, 14,872 patients of HCC treated by surgical resection between 2000 and 2005 were enrolled. We modified the current Japanese staging system for HCC, by further dividing stage IVA into stage IVAnon-n1 and stage n1, according to the absence or presence of pathologically proven lymph node metastasis. Thus, the patients classified into 6 disease stages, that is, I (n = 1494), II (n = 8056), III (n = 4243), IVAnon-n1 (n = 701), n1 (n = 112), and IVB (n = 266), and their long-term outcomes were compared. RESULTS:: The median follow-up period was 20.6 months. The 3-year overall survival rates of the patients with stage IVAnon-n1, stage n1, and stage IVB were 51.6%, 38.9% and 27.2%, respectively. A multivariate analysis showed that stage IVAnon-n1 would have a similar impact on the survival as stage n1 (hazard ratio: 0.88, 95% confidence interval: 0.59-1.33, P = 0.555), and that stage n1 still represented one class less advanced than stage IVB (hazard ratio: 0.52, 95% confidence interval: 0.34-0.80, P = 0.003). CONCLUSIONS:: The prognosis of patients with histologically node-positive HCC was similar to that of patients with locally advanced HCC (stage IVA), which supports the validity of the current Japanese staging system and also partially validates the system proposed by the UICC/AJCC.
  Annals of surgery 03/2013; · 7.90 Impact Factor
• Article: Suppression of autophagy by CDCP1 signaling is essential for anchorage-independent survival of lung cancer cells.

  Takamasa Uekita, Satoko Fujii, Yuri Miyazawa, Akinori Hashiguchi, Hitosi Abe, Michiie Sakamoto, Ryuichi Sakai
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  ABSTRACT: CUB domain-containing protein 1 (CDCP1) has been implicated in promoting metastasis of cancer cells through several mechanisms, including the inhibition of anoikis, cell death triggered by a loss of extracellular matrix interactions. However, the mechanism inhibiting cell death regulated by CDCP1 remains elusive. Inhibition of CDCP1 expression using small interfering RNA (siRNA) induced the cell death of suspended cancer cells without cleaving caspase-3, a marker of apoptosis; cell death was not inhibited by a general caspase inhibitor, suggesting that the loss of CDCP1 induces caspase-independent cell death. In contrast, knockdown of CDCP1 as well as protein kinase Cδ (PKCδ), a downstream effector of CDCP1, in a suspension culture of lung cancer cells resulted in marked induction of membranous microtubule-associated protein 1 light chain 3 (LC3)-II protein, a hallmark of autophagy and caused the formation of an autophagosome structure visualized using green fluorescent protein (GFP)-tagged LC3-II. Expression and phosphorylation of exogenous CDCP1 by Fyn kinase reduced the formation of autophagosomes and inhibited phosphorylation of CDCP1 by PP2, a Src kinase inhibitor or inhibited PKCδ by rottlerin, stimulating autophagosome formation. Moreover, death of suspended lung cancer cells induced by CDCP1 siRNA or by PKCδ siRNA was reduced by the autophagy inhibitor 3-methyladenine. These results indicate that CDCP1-PKCδ signaling plays a critical role in inhibiting autophagy, which is responsible for anoikis resistance of lung cancer cells.
  Cancer Science 03/2013; · 3.33 Impact Factor
• Article: Prognostic Impact of Spontaneous Tumor Rupture in Patients With Hepatocellular Carcinoma: An Analysis of 1160 Cases From a Nationwide Survey.

  Taku Aoki, Norihiro Kokudo, Yutaka Matsuyama, Namiki Izumi, Takafumi Ichida, Masatoshi Kudo, Yonson Ku, Michiie Sakamoto, Osamu Nakashima, Osamu Matsui, Masatoshi Makuuchi
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  ABSTRACT: OBJECTIVE:: The aim of the present study was to investigate the background characteriscs of ruptured hepatocellular carcinoma (HCC) and to clarify the true impact of tumor rupture on patient prognosis in a large patient cohort. BACKGROUND:: Spontaneous tumor rupture of HCC has been associated with a very poor patient prognosis and the current TNM staging systems classify ruptured HCC as T4 based on insufficient evidence. METHODS:: In total, 1106 patients with ruptured HCC were extracted from the database of a nationwide survey conducted in Japan from 2000 to 2005. The clinicopathological parameters associated with HCC rupture were investigated using univariate and multivariate logistic regression models. The survival curves for ruptured and nonruptured HCC were generated and compared to evaluate the impact of the event (rupture) itself on patient prognosis and the TNM staging systems. RESULTS:: The multivariate analyses showed that tumor rupture was associated with both a poor liver functional reserve and an advanced tumor status. Analyses of the survival curves stratified according to the baseline TNM staging showed that tumor rupture had an additional impact on the baseline survival curves without rupture, and the impact corresponded to the addition of 0.5 to 2 stages to the baseline tumor staging. CONCLUSIONS:: The present study suggested that tumor rupture itself had a negative impact on patient survival. However, its impact was not strong enough to cancel the effects of the other tumor-related parameters. Therefore, it may be appropriate to give additional stages to the baseline tumor staging in cases of ruptured HCC.
  Annals of surgery 03/2013; · 7.90 Impact Factor
• Article: Clinical implication of hypovascular hepatocellular carcinoma studied in 4,474 patients with solitary tumour equal or less than 3 cm.

  Kenichi Takayasu, Shigeki Arii, Michiie Sakamoto, Yutaka Matsuyama, Masatoshi Kudo, Takafumi Ichida, Osamu Nakashima, Osamu Matsui, Namiki Izumi, Yonson Ku, Norihiro Kokudo, Masatoshi Makuuchi
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  ABSTRACT: BACKGROUND & AIMS: To clarify the biological behaviour of small hypovascular hepatocellular carcinoma (HCC) because of insufficient evidence even though frequently encountered. METHODS: The study covered naïve 4,474 patients who met solitary HCC ≤3 cm (mean, 2.1 cm), histopathologically proven and Child Pugh A or B. Macroscopic vascular invasion and distant metastasis were excluded. The hypovascularity of tumour was defined as hypo- or iso-enhancement in arterial phase of multiple dynamic imaging techniques. RESULTS: Of them, 802 (18%) were hypovascular. The ratio of hypovascular HCC decreased as tumour size increased (P < 0.001) and most of them developed to hypervascular type when they grew over 1.5 cm. Hypovascular group showed a significantly higher ratio of well differentiated grade (P < 0.001) and marginally less incidence of microvascular invasion and metastases compared with hypervascular group. The histologic dedifferentiation (less differentiation) developed step-by-step as tumour size increased in hyper- and even hypovascular group. The des-γ-carboxy prothrombin (DCP) value ≥ 300mAU/ml was closely correlated with increase of tumour size in both groups. Logistic regression analysis revealed five variables were independent predictors for hypovascular HCC; tumour size ≤1.5 cm, alpha-fetoprotein < 200 ng/ml, DCP < 40mAU/ml, well differentiated grade, and positivity for hepatitis C virus antibody. CONCLUSIONS: Hypovascular HCC was biologically less aggressive and developed with stepwise dedifferentiation and transformation to hypervascular appearance along with tumour growth. These results will help in leading correct diagnosis of small hypovascular tumour and assessing optimal treatment for hypovascular HCC≤3 cm.
  Liver international: official journal of the International Association for the Study of the Liver 01/2013; · 3.82 Impact Factor
• Article: Role of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic Acid-enhanced magnetic resonance imaging in the management of hepatocellular carcinoma: consensus at the symposium of the 48th annual meeting of the liver cancer study group of Japan.

  Masatoshi Kudo, Osamu Matsui, Michiie Sakamoto, Azusa Kitao, Tonsok Kim, Shun-Ichi Ariizumi, Tomoaki Ichikawa, Satoshi Kobayashi, Yasuharu Imai, Namiki Izumi, Yasunari Fujinaga, Shigeki Arii
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  ABSTRACT: We summarize here the consensus reached at the Symposium of the 48th Annual Meeting of the Liver Cancer Study Group of Japan held in Kanazawa on July 20th and 21st, 2012, on the role of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) in the management of hepatocellular carcinoma (HCC). Currently, dynamic CT is the first choice of imaging modality when HCC is suspected. EOB-MRI is useful for differentiation and definitive diagnosis of HCC when dynamic CT/MRI does not show conclusive findings for HCC. In addition, contrast- enhanced ultrasound with Sonazoid is useful for making a decision on whether or not to treat a hypovascular lesion <1 cm when the nodules are shown with low intensity in the hepatocyte phase of EOB-MRI. Furthermore, EOB-MRI should be performed in selected cases of HCC ultrahigh-risk groups every 3-4 months, or EOB-MRI should be performed at least once at the first visit in all HCC ultrahigh-risk groups.
  Oncology 01/2013; 84 Suppl 1:21-7. · 2.27 Impact Factor
• Article: Nuclear Localization of CD26 Induced by a Humanized Monoclonal Antibody Inhibits Tumor Cell Growth by Modulating of POLR2A Transcription.

  Kohji Yamada, Mutsumi Hayashi, Hiroko Madokoro, Hiroko Nishida, Wenlin Du, Kei Ohnuma, Michiie Sakamoto, Chikao Morimoto, Taketo Yamada
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  ABSTRACT: CD26 is a type II glycoprotein known as dipeptidyl peptidase IV and has been identified as one of the cell surface markers associated with various types of cancers and a subset of cancer stem cells. Recent studies have suggested that CD26 expression is involved in tumor growth, tumor invasion, and metastasis. The CD26 is shown in an extensive intracellular distribution, ranging from the cell surface to the nucleus. We have previously showed that the humanized anti-CD26 monoclonal antibody (mAb), YS110, exhibits inhibitory effects on various cancers. However, functions of CD26 on cancer cells and molecular mechanisms of impaired tumor growth by YS110 treatment are not well understood. In this study, we demonstrated that the treatment with YS110 induced nuclear translocation of both cell-surface CD26 and YS110 in cancer cells and xenografted tumor. It was shown that the CD26 and YS110 were co-localized in nucleus by immunoelectron microscopic analysis. In response to YS110 treatment, CD26 was translocated into the nucleus via caveolin-dependent endocytosis. It was revealed that the nuclear CD26 interacted with a genomic flanking region of the gene for POLR2A, a subunit of RNA polymerase II, using a chromatin immunoprecipitation assay. This interaction with nuclear CD26 and POLR2A gene consequently led to transcriptional repression of the POLR2A gene, resulting in retarded cell proliferation of cancer cells. Furthermore, the impaired nuclear transport of CD26 by treatment with an endocytosis inhibitor or expressions of deletion mutants of CD26 reversed the POLR2A repression induced by YS110 treatment. These findings reveal that the nuclear CD26 functions in the regulation of gene expression and tumor growth, and provide a novel mechanism of mAb-therapy related to inducible translocation of cell-surface target molecule into the nucleus.
  PLoS ONE 01/2013; 8(4):e62304. · 4.09 Impact Factor
• Article: Comparison of resection and ablation for hepatocellular carcinoma: a cohort study based on a Japanese nationwide survey.

  Kiyoshi Hasegawa, Norihiro Kokudo, Satoshi Makuuchi, Namiki Izumi, Takafumi Ichida, Masatoshi Kudo, Yonson Ku, Michiie Sakamoto, Osamu Nakashima, Osamu Matsui, Yutaka Matsuyama
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  ABSTRACT: BACKGROUND & AIMS: The treatment of choice for early or moderately advanced hepatocellular carcinoma (HCC) with good liver function remains controversial. We evaluated the therapeutic impacts of surgical resection (SR), percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA) on long-term outcomes in patients with HCC. METHODS: A database constructed on the basis of a Japanese nationwide survey of 28,510 patients with HCC treated by SR, PEI, or RFA between 2000 and 2005 was used to identify 12,968 patients who had no more than 3 tumors (⩽3cm) and liver damage of class A or B. The patients were divided into SR (n=5,361), RFA (n=5,548), and PEI groups (n=2,059). Overall survival and time to recurrence were compared among them. RESULTS: Median follow-up was 2.16 years. Overall survival at 3 and 5 years were respectively 85.3%/71.1% in the SR group, 81.0%/61.1% in the RFA, and 78.9%/56.3% in the PEI. Time to recurrence at 3 and 5 years were 43.3%/63.8%, 57.2%/71.7%, and 64.3%/76.9%, respectively. On multivariate analysis, the hazard ratio for death was significantly lower in the SR group than in the RFA (SR vs. RFA:0.84, 95% confidence interval, 0.74-0.95; P=0.006) and the PEI (SR vs. PEI:0.75, 0.64-0.86; P=0.0001). The hazard ratios for recurrence were also lower in the SR group than in the RFA (SR vs. RFA:0.74, 0.68-0.79; P=0.0001) and the PEI (SR vs. PEI:0.59, 0.54-0.65; P=0.0001). CONCLUSIONS: Our findings suggest that surgical resection results in longer overall survival and shorter time to recurrence than either RFA or PEI in patients with HCC.
  Journal of Hepatology 11/2012; · 9.26 Impact Factor
• Article: Computational grading of hepatocellular carcinoma using multifractal feature description.

  Chamidu Atupelage, Hiroshi Nagahashi, Masahiro Yamaguchi, Tokiya Abe, Akinori Hashiguchi, Michiie Sakamoto
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  ABSTRACT: Cancer grading has become an important topic in the field of image interpretation-based computer aided diagnosis systems. This paper proposes a novel feature descriptor to observe the characteristics of histopathological textures in a discriminative manner. The proposed feature descriptor utilizes fractal geometric analysis with four multifractal measures to construct an eight dimensional feature space. The proposed method employed a bag-of-feature-based classification model to discriminate a set of hepatocellular carcinoma images into five categories according to Edmondson and Steiner's grading system. Three feature selection methods were utilized to obtain the most discriminative features of codeword dictionary (codebook). Furthermore, we incorporated four other textural feature descriptors: Gabor-filters, LM-filters, local binary patterns, and Haralick, to obtain a benchmark of the accuracy of the classification. Two experiments were performed: (i) classifying non-neoplastic tissues and tumors and (ii) grading the hepatocellular carcinoma images into five classes. Experimental results indicated the significance of the multifractal features for describing the histopathological image texture because it outperformed other four feature descriptors. We graded a given ROI image by defining a threshold-based majority-voting rule and obtained an average correct classification rate around 95% for five classes classification.
  Computerized medical imaging and graphics: the official journal of the Computerized Medical Imaging Society 11/2012; · 1.04 Impact Factor
• Article: Leucine-rich repeat-containing G protein-coupled receptor 5 regulates epithelial cell phenotype and survival of hepatocellular carcinoma cells.

  Mariko Fukuma, Keiji Tanese, Kathryn Effendi, Ken Yamazaki, Yohei Masugi, Mariko Suda, Michiie Sakamoto
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  ABSTRACT: The leucine-rich repeat containing G protein-coupled receptor 5 (LGR5), also known as GPR49, is a seven-transmembrane receptor that is expressed in stem cells of the intestinal crypts and hair follicles of mice. LGR5 is overexpressed in some types of human cancer, and is one of the target genes of the Wnt signaling pathway. To explore the function of LGR5 in cancer cells, stable hepatocellular carcinoma (HCC) cell lines expressing FLAG-tagged LGR5 were established. Overexpression of LGR5 resulted in changes in cell shape from an extended flat (mesenchymal) phenotype to a round aggregated (stem cell-like) phenotype. Cells transfected with LGR5 showed higher colony forming activity, and were more resistant to a cytotoxic drug than cells transfected with empty vector. Overexpression of LGR5 inhibited cell motility. LGR5-transfected cells formed nodule type tumors in the livers of immunodeficient mice, whereas empty vector-transfected cells formed more invasive tumors. Down-regulation of LGR5 changed the morphology of HCC cells from the aggregated phenotype to an extended spindle phenotype, and cell motility was increased. This is the first study reporting the functional role of LGR5 in the biology of HCC cells, and the results suggest that aberrant expression of LGR5 regulates epithelial cell phenotype and survival.
  Experimental Cell Research 11/2012; · 3.58 Impact Factor
• Article: Impact of the Integrin Signaling Adaptor Protein NEDD9 on Prognosis and Metastatic Behavior of Human Lung Cancer.

  Shunsuke Kondo, Satoshi Iwata, Taketo Yamada, Yusuke Inoue, Hiromi Ichihara, Yoshiko Kichikawa, Tomoki Katayose, Akiko Souta-Kuribara, Hiroto Yamazaki, Osamu Hosono, Hiroshi Kawasaki, Hirotoshi Tanaka, Yuichiro Hayashi, Michiie Sakamoto, Kazunori Kamiya, Nam H Dang, Chikao Morimoto
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  ABSTRACT: PURPOSE: In a substantial population of non-small cell lung cancer (NSCLC), expression and activation of EGF receptor (EGFR) have been reported and is regarded as a novel molecular target. A growing body of evidence has shown the signaling crosstalk between EGFR and integrins in cellular migration and invasion. NEDD9 is an integrin signaling adaptor protein composed of multiple domains serving as substrate for a variety of tyrosine kinases. In the present study, we aimed at elucidating a role of NEDD9 in the signaling crosstalk between EGFR and integrins.EXPERIMENTAL DESIGN: Using NSCLC cell lines, we conducted immunoblotting and cellular migration/invasion assay in vitro. Next, we analyzed metastasis assays in vivo by the use of xenograft transplantation model. Finally, we retrospectively evaluated clinical samples and records of patients with NSCLCs.RESULTS: We showed that tyrosine phosphorylation of NEDD9 was reduced by the inhibition of EGFR in NSCLC cell lines. Overexpression of constitutively active EGFR caused tyrosine phosphorylation of NEDD9 in the absence of integrin stimulation. By gene transfer and gene knockdown, we showed that NEDD9 plays a pivotal role in cell migration and invasion of those cells in vitro. Furthermore, overexpression of NEDD9 promoted lung metastasis of an NSCLC cell line in NOD/Shi-scid, IL-2Rγ(null) mice (NOG) mice. Finally, univariate and multivariate Cox model analysis of NSCLC clinical specimens revealed a strong correlation between NEDD9 expression and recurrence-free survival as well as overall survival.CONCLUSION: Our data thus suggest that NEDD9 is a promising biomarker for the prognosis of NSCLCs and its expression can promote NSCLC metastasis. Clin Cancer Res; 1-13. ©2012 AACR.
  Clinical Cancer Research 10/2012; · 7.74 Impact Factor
• Article: Li-Fraumeni syndrome with simultaneous osteosarcoma and liver cancer: Increased expression of a CD44 variant isoform after chemotherapy.

  Go J Yoshida, Yasushi Fuchimoto, Tomoo Osumi, Hiroyuki Shimada, Seiichi Hosaka, Hideo Morioka, Makio Mukai, Yohei Masugi, Michiie Sakamoto, Tatsuo Kuroda
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  ABSTRACT: BACKGROUND: Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome that is commonly associated with a germline mutation in the tumor suppressor gene p53. Loss of p53 results in increased expression of CD44, a cancer stem cell (CSC) marker, which is involved in the scavenging of reactive oxygen species (ROS). Here, we report a change in the expression of a CD44 variant isoform (CD44v8-10) in an 8-year-old female LFS patient with osteosarcoma and atypical liver cancer after chemotherapy. CASE PRESENTATION: The patient visited a clinic with a chief complaint of chronic pain in a bruise on her right knee. Magnetic resonance imaging (MRI) raised the possibility of a bone malignancy. Biochemical testing also revealed significantly elevated levels of AFP, which strongly suggested the existence of a primary malignancy in the liver. MRI imaging showed the simultaneous development of osteosarcoma and liver cancer, both of which were confirmed upon biopsy. Combined therapy with surgical resection after chemotherapy was successful in this patient. Regardless of the absence of a familial history of hereditary cancer, a germline mutation in p53 was identified (a missense mutation defined as c.722 C>T, p.Ser241Phe). To better understand the cancer progression and response to treatment, immunohistochemical (IHC) analysis of biopsy specimens obtained before and after chemotherapy was performed using a specific antibody against CD44v8-10. CONCLUSION: This case demonstrates the ectopic up-regulation of CD44v8-10 in a biopsy sample obtained after cytotoxic chemotherapy, which confers high levels of oxidative stress on cancer cells. Because the alternative splicing of CD44 is tightly regulated epigenetically, it is possible that micro-environmental stress resulting from chemotherapy caused the ectopic induction of CD44v8-10 in vivo.
  BMC Cancer 10/2012; 12(1):444. · 3.01 Impact Factor
• Article: Involvement of hepatocellular carcinoma biomarker, cyclase-associated protein 2 in zebrafish body development and cancer progression.

  Kathryn Effendi, Ken Yamazaki, Taisuke Mori, Yohei Masugi, Shinji Makino, Michiie Sakamoto
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  ABSTRACT: Cyclase-associated protein 2 (CAP2) is a conserved protein that is found up-regulated in hepatocellular carcinoma (HCC). By using zebrafish, combined with HCC cell lines, we further investigated the role of CAP2. The zebrafish CAP2 sequence was 60% identical to human CAP2 with 77% homology in the C-terminal actin-binding domain, and 58% in the N-terminal cyclase-binding domain. CAP2 expression was observed during zebrafish development and was preferentially expressed in the skeletal muscle and heart. Knockdown using two different morpholinos against CAP2 resulted in a short-body morphant zebrafish phenotype with pericardial edema. CAP2 was observed co-localized with actin in zebrafish skeletal muscle, and in the leading edge of lamellipodium in HCC cell lines. CAP2 silencing resulted in a defect in lamellipodium formation and decreased cell motility in HCC cell lines. Strongly positive expression of CAP2 was observed in 10 of 16 (63%) poorly, 30 of 68 (44%) moderately, and 2 of 21 (10%) well differentiated HCC. CAP2 expression was significantly associated with tumor size, poor differentiation, portal vein invasion, and intrahepatic metastasis. Our results indicate that an important conserved function of CAP2 in higher vertebrates may be associated with the process of skeletal muscle development. CAP2 also played an important role in enhancing cell motility, which may promote a more invasive behavior in the progression of HCC. These findings highlight the link between development and cancer.
  Experimental Cell Research 09/2012; · 3.58 Impact Factor
• Article: Integrative array-based approach identifies MZB1 as a frequently methylated putative tumor suppressor in hepatocellular carcinoma.

  Satoshi Matsumura, Issei Imoto, Ken-ichi Kozaki, Takeshi Matsui, Tomoki Muramatsu, Mayuko Furuta, Shinji Tanaka, Michiie Sakamoto, Shigeki Arii, Johji Inazawa
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  ABSTRACT: The aim of this study was the identification of novel tumor suppressor genes (TSG) silenced by DNA hypermethylation in hepatocellular carcinoma (HCC). We conducted integrative array-based approach for genome-wide screening of methylation targets using a methylated DNA immunoprecipitation-CpG island microarray and expression array in three universal hepatoma cell lines and normal liver tissue. Through detailed expression and functional analyses using hepatoma cell lines and primary HCC samples, we isolated novel TSGs for HCC. A total of 642 genes were identified as methylated in three hepatoma cell lines but unmethylated in normal liver tissue, whereas 204 genes on autosomes were identified as genes unexpressed but restored after treatment with 5-aza-2'-deoxycytidine in these cell lines and expressed in normal tissue. Through the integration of results of the two-array analyses and further validation analyses of expression and methylation status in 17 cell lines and 30 primary tumors of hepatoma, we identified MZB1, marginal zone B and B1 cell-specific protein, encoding an endoplasmic reticulum protein, as a putative TSG frequently methylated within its CpG island in hepatoma. Among 162 patients with primary HCC, silencing of MZB1 protein was significantly and independently associated with a worse outcome. Restoration of MZB1 expression in hepatoma cells reduced cell proliferation in vitro and in vivo through G(1)-arrest. These results suggest that methylation-mediated silencing of MZB1 expression leads to loss of its tumor-suppressive activity, which may be a factor in the hepatocarcinogenesis, and is a useful prognosticator in HCC.
  Clinical Cancer Research 05/2012; 18(13):3541-51. · 7.74 Impact Factor
• Article: Neutrophil elastase inhibitor improves survival rate after ischemia reperfusion injury caused by supravisceral aortic clamping in rats.

  Naoki Fujimura, Hideaki Obara, Koichi Suda, Hiroya Takeuchi, Taku Miyasho, Kazufumi Kawasako, Wenlin Du, Shingo Yamada, Shigeshi Ono, Kenji Matsumoto, Sachiko Matsuda, Hiroshi Yagi, Minoru Kitago, Masahiro Shinoda, Osamu Itano, Minoru Tanabe, Michiie Sakamoto, Ikuro Maruyama, Yuko Kitagawa
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  ABSTRACT: BACKGROUND: Sivelestat sodium hydrate is a specific neutrophil elastase inhibitor effective in acute lung injury (ALI) associated with systemic inflammatory response syndrome. Bowel ischemia reperfusion injury (IRI) induced by supravisceral aortic clamping is associated with an excessive systemic inflammatory response, resulting in remote organ damage, including ALI. In this study, we investigated whether sivelestat can attenuate neutrophil sequestration in the lung, alleviate ALI, and improve survival in a rat bowel IRI model. METHODS: Adult male Sprague-Dawley rats underwent bowel IRI induced by supravisceral aortic clamping and were randomly assigned to receive sivelestat or saline (control) and monitored for survival. We randomly assigned other rats to undergo laparotomy alone (sham operation), IRI alone, or IRI and sivelestat treatment. We evaluated blood samples for organ function, cytokine levels, and neutrophil elastase activity after reperfusion. Organs were analyzed histologically. We also determined lung injury in another set of rats. RESULTS: Bowel IRI induced a significant increase in serum variables indicative of organ function, cytokine concentrations, neutrophil elastase activity, and lung permeability and edema, which reflected the presence of both systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome. Treatment with sivelestat significantly improved survival rate, lung permeability and edema, and significantly decreased levels of creatinine, interleukin 6, interleukin 10, and neutrophil elastase activity. Histological studies showed that sivelestat-treated rats had less bowel IRI-induced damage to lung and liver tissue than controls. CONCLUSION: In a rat model, administration of sivelestat attenuated the effects of bowel IRI induced by supravisceral aortic clamping, and improved the survival rate.
  Journal of Surgical Research 05/2012; · 2.25 Impact Factor
• Article: Bouveret’s syndrome with a concomitant incidental T1 gallbladder cancer

  Masahiro Shinoda, Koichi Aiura, Yoshiyuki Yamagishi, Yohei Masugi, Kiminori Takano, Shotaro Maruyama, Tomoyuki Irino, Kaoru Takabayashi, Yoshinori Hoshino, Shin Nishiya, Taizo Hibi, Shigeyuki Kawachi, Minoru Tanabe, Masakazu Ueda, Michiie Sakamoto, Toshifumi Hibi, Yuko Kitagawa
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  ABSTRACT: Bouveret’s syndrome, which is a gastric outlet obstruction caused by a gallstone in the duodenum, is a rare complication of gallstone disease. We report a case of Bouveret’s syndrome in an 81-year-old woman who also exhibited incidental gallbladder cancer. She was admitted to our hospital complaining of upper abdominal pain and vomiting. A computed tomography examination showed a cholecystoduodenal fistula, a large impacted stone at the gastric outlet, and a dilated stomach. She was diagnosed as having Bouveret’s syndrome. The patient underwent an upper gastrointestinal endoscopy and a mechanical lithotripsy was successfully performed for the stone. She then underwent a cholecystectomy with primary closure of the duodenal fistula. An intra-operative histopathology examination revealed severe cholecystitis with an adenocarcinoma in part of the gallbladder. Gallbladder bed resection and regional lymph node dissection were also performed. To the best of our knowledge, this is the first published report of a case in which Bouveret’s syndrome and gallbladder cancer co-existed. KeywordsBouveret’s syndrome-Cholecystoduodenal fistula-Gallbladder cancer-Gallstone-Gastric outlet obstruction
  Clinical Journal of Gastroenterology 04/2012; 3(5):248-253.
• Article: Proposed indications for limited resection of early ampulla of Vater carcinoma: clinico-histopathological criteria to confirm cure.

  Koichi Aiura, Taizo Hibi, Hiroto Fujisaki, Minoru Kitago, Minoru Tanabe, Shigeyuki Kawachi, Osamu Itano, Masahiro Shinoda, Hiroshi Yagi, Yohei Masugi, Michiie Sakamoto, Yuko Kitagawa
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  ABSTRACT: BACKGROUND: Limited resection is reserved for patients with high operative risk or benign adenomas. We aimed to define indications for limited resection of early ampulla of Vater carcinoma with curative intent through detailed preoperative examinations and histopathological evaluations. METHODS: We performed a retrospective cohort study of all consecutive Japanese patients who underwent resection for ampulla of Vater neoplasms at our hospital from 1986 to 2010. RESULTS: A total of 75 patients were identified. Moderately/poorly differentiated histology, lympho-vascular/perineural invasion, and duodenal/pancreatic invasion were significant risk factors for lymph node metastases. Macroscopically, non-exposed protruded- or ulcerative-type disease did not correlate directly with lymph node metastases; however, these tumor types were associated with other invasive features. In a subset of early carcinomas fulfilling the conditions of exposed protruded adenoma or papillary/well-differentiated adenocarcinoma determined by endoscopic biopsy, negative duodenal invasion determined by endoscopic ultrasonography, no tumor infiltration into the pancreatic duct determined by intraductal ultrasound, and diameter of the pancreatic duct ≤3 mm determined by endoscopic retrograde cholangiopancreatography (N = 11), the incidence of lymph node metastasis and tumor infiltration into the pancreatic duct was 0%. CONCLUSION: Strictly selected patients with early ampulla of Vater carcinomas may benefit from limited resection if the resected specimen is evaluated to confirm all histopathological criteria.
  Journal of hepato-biliary-pancreatic sciences. 12/2011;
• Article: Superselective transarterial chemoembolization for hepatocellular carcinoma. Validation of treatment algorithm proposed by Japanese guidelines.

  Kenichi Takayasu, Shigeki Arii, Masatoshi Kudo, Takafumi Ichida, Osamu Matsui, Namiki Izumi, Yutaka Matsuyama, Michiie Sakamoto, Osamu Nakashima, Yonson Ku, Norihiro Kokudo, Masatoshi Makuuchi
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  ABSTRACT: Transcatheter arterial chemoembolization with lipiodol (TACE) is widely performed in patients with hepatocellular carcinoma (HCC) unsuitable for curative treatment. It has recently been recommended for patients with 2 or 3 tumors >3 cm or ≥4 tumors in a treatment algorithm proposed by Japanese guidelines. However, the best indication and appropriateness of the algorithm for TACE are still unclear. In 4966 HCC patients who underwent TACE, survival was evaluated based on tumor number, size and liver function; and the adequacy of the algorithm for TACE was validated. Exclusion criteria were: vascular invasion, extrahepatic metastasis, and prior treatment. The mean follow up period was 1.6 years. The overall median and 5-year survivals were 3.3 years and 34%, respectively. Multivariate analysis revealed that Child-Pugh class, tumor number, size, alpha-fetoprotein, and des-gamma carboxy-prothrombin were independent predictors. The survival rate decreased as the tumor number (p=0.0001) and size increased (p=0.04 to p=0.0001) in all but one subgroup in both Child-Pugh-A and -B. The stratification of these patients to four treatments in the algorithm showed potential ability to discriminate survivals of the resection and ablation (non-TACE) groups from those of the TACE group in Child-Pugh-B and partially in A. TACE showed higher survival rates in patients with fewer tumor numbers, smaller tumor size, and better liver function. The treatment algorithm proposed by the Japanese guidelines might be appropriate to discriminate the survival of patients with non-TACE from TACE therapy.
  Journal of Hepatology 12/2011; 56(4):886-92. · 9.26 Impact Factor